Nancy A. Melville

June 17, 2014

MILAN — Low-dose thalidomide is effective in the treatment of epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT) who have failed to respond to other treatments, results from a new study show. However, some patients might require maintenance therapy.

Severe, recurrent bleeding from the nose is the most common presentation of HHT, but an effective treatment for the condition, which can be severe enough to lead to anemia, is lacking, said lead investigator Rosangela Invernizzi, MD, from the IRCCS Policlinico San Matteo Foundation at the University of Pavia in Italy.

"In the management of HHT epistaxis, multiple approaches have been tried, but currently there is no established medical treatment available for these patients," she told Medscape Medical News. "Surgical options are largely palliative, with variable and temporary results. Thalidomide therapy could become an important medical option and address unmet medical need."

Because angiogenesis is involved in the pathogenesis of HHT, the investigators decided to evaluate the antiangiogenic agent thalidomide as a potential treatment.

Dr. Invernizzi presented the study results during the Presidential/Best Abstracts Symposium here at the 19th Congress of the European Hematology Association.

In the study, 17 men and 11 women (median age, 64 years) with HHT received oral thalidomide 50 mg daily.

All patients had had at least 1 episode of overt bleeding that required at least 1 blood transfusion each week in the previous 3 months, and all were nonresponsive to surgical procedures.

Patients were evaluated every 4 weeks, and the dose was increased by 50 mg per day until a complete or partial response was achieved. The maximum dose was 200 mg daily.

After a response was achieved, thalidomide was continued for another 16 weeks. Median follow-up was 62 weeks (range 3 - 117 weeks).

In all 26 evaluable patients, the treatment was effective; 16 (62%) responded within 4 weeks of starting the drug and 10 (38%) achieved a partial response after 8 weeks of treatment.

Four patients experienced a cessation of epistaxis and 12 had a reduction in severity.

Hemoglobin levels were significantly higher after the treatment (P = .04), and the need for transfusions decreased, resulting in improvements in the quality of life.

Twenty patients completed the full treatment regimen.

At a median of 51 weeks after the therapy ended, 9 patients remained stable without a reduction in response and 11 relapsed; median time to relapse was 43 weeks.

For 4 of the patients who relapsed, additional treatment with thalidomide 50 to 100 mg per day for 8 weeks resulted in a favorable response and was not associated with adverse effects. Their improvement was sustained at follow-ups from 8 to 30 weeks.

The most common drug-related adverse effects were gastrointestinal, including constipation, vomiting, or mouth dryness, which affected 15 patients, and drowsiness, which affected 9 patients.

No associations were found between genetic or clinical features and the time to response or duration of response.

"In HHT, many types of gene mutations, partly unknown, are responsible for vascular malformations," Dr. Invernizzi explained.

"The mechanisms by which thalidomide inhibits bleeding from vascular malformations are not completely clear. Thus, studies are warranted to better define both the mechanisms of action and the risk factors for relapse," she said.

One aspect of thalidomide that is all-too-well understood is the potential for notorious adverse effects if taken during pregnancy.

"Thalidomide should be used with extreme caution, owing to the potential severe, generally dose-dependent, adverse effects," she said. "Given its teratogenic effects and considering other potentially serious side effects, thalidomide is used only under strict guidelines and very careful monitoring."

"Further research should be directed toward identifying efficacy, tolerance, safety, and posology for long-term use of the drug to prevent relapse," Dr. Invernizzi said.

An effective treatment for epistaxis in HHT would be an important development for the disease, said Cheng-Hock Toh, MB, ChB, MD, from the Department Clinical Infection, Microbiology, and Immunology at the University of Liverpool in the United Kingdom.

"This would be the first modulatory treatment to reduce a troublesome symptom in these patients, which can lead to anemia," he told Medscape Medical News.

"Hitherto, epistaxis is usually managed with nasal cautery, which after a few times becomes of limited value. As this is a lifelong condition, successful drug treatment will have an impact," Dr. Toh explained.

The risks to pregnant women, however, should be underscored. "It is important that women of child-bearing age are aware of the well-known dangers of thalidomide," he said.

The study received support from Telethon Grant GGP13036. Dr. Invernizzi and Dr. Toh have disclosed no relevant financial relationships.

19th Congress of the European Hematology Association (EHA): Abstract S692. Presented June 14, 2014.


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